Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
  • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
  • C07K14/245—Escherichia (G)
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
  • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/10—Tetrapeptides
  • C07K5/1002—Tetrapeptides with the first amino acid being neutral
  • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
  • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to new lipopeptides and in particular to compounds of the formula wherein R 1 is an unsubstituted or at most on one of the carbon atoms not adjacent to the sulfur atom by a free or a hydroxy group esterified with a monobasic carboxylic acid and optionally interrupted by one or more oxygen atoms in the carbon atom chain, saturated or unsaturated aliphatic hydrocarbon radical with at least 9 carbon atoms, which can also be substituted by a maximum of 2 cycloaliphatic hydrocarbon radicals with 5-8 ring carbon atoms, or the radical -CO-R 1 ', wherein R 1 ' is a saturated or unsaturated, aliphatic or mixed aliphatic-cycloaliphatic hydrocarbon radical, optionally also interrupted by oxygen atoms in the carbon atom chain, with 11-21 carbon atoms, or represents 5-cholesten-3-yl, R 2 represents a saturated or unsaturated, aliphatic or mixed aliphatic cycloaliphatic
• Lipopeptides have already been described as degradation fragments of lipoproteins.
• Hantke and Braun (Eur. J. Biochem. 34, 284-296 (1973), for example, were able to isolate lipopeptides or lipopeptide mixtures in an impure form from the murein lipoprotein of the outer cell wall of Escherichia coli by enzymatic degradation, according to their investigations the following structure or corresponding formulas with a shortened polypeptide chain, Y 1 , Y 2 , Y 3 are acyl radicals of various higher saturated and unsaturated fatty acids, such as those with 14-19 C atoms and others.
• the Murein-Pro has the same structure tein as such (loc.cit.), the absolute configuration of the two asymmetric carbon atoms of the above formula not being investigated. Both the murein lipopratein and its degradation products show a mitogenic effect in vitro against mouse lymphocytes. [See. also Z. Immun.-Forschung, Vol. 153, pp. 11-22 (1977)].
• the degradation lipopeptides obtained from murein protein contain the "glycerylcysteine" underlying.
• these fragments were not products with a well-defined composition and were obviously complicated mixtures of condensation products from the peptide portion mentioned and very different acyl derivatives of glycerylcysteine.
• the lipopeptides of the present application now differ from those degradation products of murein proteins in many ways: they provide lipopeptides of well-defined uniform chemical constitution and configuration are that are synthetically ga n g Lich and are therefore suitable for therapeutic use Instead of the esterified portion of glycerin in the "glyceryl cysteine" there is a larger hydrocarbon residue which may have ether groups and which has a maximum of only one free or esterified Hy droxyily, or higher alicyclic hydrocarbon radicals.
• the amino acid sequence can also be different from that given above for the known degradation lipcpeptide mixtures in formula (II), or only a single amino acid can be present in its place, and derivatives such as amides and esters of the terminal carboxyl group are used. includes. While in the known mixtures of lipopeptides mentioned the configuration on the cysteine is only R, it can also be S in the compounds according to the present application.
• R 1 is a radical
• R 3 is an unsubstituted or at most substituted by a free or a hydroxyl group esterified with a monobasic carboxylic acid and optionally interrupted by one or more oxygen atoms in the carbon atom chain, saturated or unsaturated aliphatic hydrocarbon radical having at least 12 carbon atoms, the can also be substituted by a maximum of 2 cycloaliphatic hydrocarbon radicals having 5 to 8 ring carbon atoms.
• the aliphatic hydrocarbon radicals R or R 3 mentioned or their derivatives mentioned, which are substituted by oxygen functions or interrupted by oxygen atoms and / or substituted by cycloaliphatic hydrocarbons, can be saturated or unsaturated, straight-chain or branched, and preferably have a total of not more than 60 C atoms .
• the branched residues there are in particular those before moves in which there is at least one straight chain with 12-24 carbon atoms, which can optionally be substituted by other shorter chains.
• a plurality of isolated and / or conjugated double bonds can be present in the unsaturated radicals, preferably 1-2 each per straight chain, in particular 2 conjugated double bonds.
• the aliphatic hydrocarbon radicals mentioned are preferably alkyl, alkenyl or alkadienyl radicals having the preferred constitution and / or number of carbon atoms mentioned.
• Alkyl groups R - are, for example, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heneicosyl and n-docosyl or the radicals substituted on one or more non-terminal C atoms thereof by methyl or ethyl .
• Alkenyl groups R l are derived, for example, from these alkyl groups and are, for example, ll-dodecenyl, 13-tetradecenyl, 14 - pentadecenyl, 15-hexadecenyl, 16-heptadecenyl, 17-octadecenyl, 18-nonadecenyl, 20-eicosenyl or one of their isomeric residues the double bond elsewhere, such as 9-octadecenyl, 8-docosenyl, or, in particular, the alkenyl derived from phytol, 3,7, 11,15-tetramethyl-2-hexadecenyl.
• a hydrocarbon group R 1 can also carry a maximum of 2 cycloaliphatic hydrocarbon radicals which have rings with 5-8 C atoms and can be unsubstituted or substituted by lower alkyl groups with 1-7 C atoms, in particular methyl groups.
• such alicyclic rings are cyclohexyl rings or their unsaturated derivatives such as cyclohexenyl or cyclohexadienyl.
• a hydrocarbon radical R 3 can also be one of these alkyl, alkenyl or alka-poly-enyl radicals.
• An alkyl radical R 3 is in particular one of the formula wherein at least one of the substituents R 4 , R 5 , R 6 is alkyl, alkenyl or alkadienyl with a straight chain of 12-24 carbon atoms, which can optionally be substituted by methyl or ethyl groups, and the other optionally hydrogen or lower are alkyl or alkenyl radicals with 1-7 C atoms, such as in particular methyl, ethyl, propyl, butyl, isopropyl, n-hexyl or n-heptyl.
• the long-chain alkyl, alkenyl or alka-poly-enyl radicals mentioned here can also be those which are particularly emphasized above.
• the radical R 1 can then also represent the 5-cholen-3-yl radical, that is to say the radical of the cholesterol which is bonded in the 3-position to the sulfur atom of the cysteine component in the compounds of the formula (I).
• the hydrocarbon radicals R 1 and R3 mentioned can also be interrupted by oxygen atoms in the carbon atom chain; in this case they represent ether radicals, it being possible for one or more -O groups to be present, in the latter case such groups being separated by a chain of at least 2 carbon atoms.
• the preferred ether groups are also derived from the hydrocarbon radicals which are particularly emphasized above. Thus, there are, for example, polyethylene glycol residues with the number of carbon atoms mentioned above for the alkyl groups mentioned to draw.
• ether groups are present in the long-chain alkyl, alkenyl or alka-poly-enyl radicals mentioned and / or in one of the lower aliphatic alkyl or alkenyl radicals mentioned with 1-7 carbon atoms.
• the lower alkyl mentioned - or alkenyl radicals are ether groups preferably at the free end of the carbon chain, in particular as methoxy groups.
• the radical R 1 in formula (I) can also mean a group -CO-R 1 ', in which R l ' represents a saturated or unsaturated, aliphatic or mixed aliphatic-cycloaliphatic hydrocarbon radical having 11-21 C atoms.
• this radical can be one of the radicals mentioned for formula (IV) or (V), but the number of carbon atoms is at most 21.
• the preferred radicals are also those highlighted above for the groups of the formulas (IV) and (V). These radicals can also be interrupted in the carbon atom chain by -0 groups, and the ether groups thus formed can in turn be those which are particularly emphasized above.
• a radical R 1 ' can also be one of the radicals described below according to formula (VI) or (VIII).
• the invention particularly relates to compounds according to formula (I) and their derivatives in which the rest R 1 has the following formula wherein X 1 and X 2 are each alkyl or alkenyl with 12-20 C atoms, R 7 is hydrogen or alkyl or alkenyl with 12-20 C atoms or the radical -CH 2 -OX 3 , where X 3 is alkyl or alkenyl with 12-20 C atoms mean, one of the groups highlighted in particular being suitable as alkyl or alkenyl.
• R 7 represents hydrogen or the radical -CH 2 -OX 3 mentioned .
• the alkyl or alkenyl groups X 1 , X 2 , X 3 can be identical to one another or different from one another. Preferred are compounds in which both groups X 1 , X 2 or all three groups X1 , X 2 , X 3 are the same, and these are preferably hexadecyl, octadecyl or docosanyl.
• a further -0 group can also be present in one or more of the above radicals X 1 , X2 , X3 , in particular such that a terminal methoxy or alkoxy group in these residues is formed.
• the groups W are in particular methyl.
• the radical R 1 can also be substituted by at most one free or one hydroxyl group esterified with a monocarboxylic acid.
• Suitable monocarboxylic acids are in particular those of the aliphatic series, in particular lower aliphatic carboxylic acids with 1-7 C atoms, such as, for example, acetic or propionic acid, butyric acids, valeric acids, caproic acids.
• the esterified hydroxyl group can also be derived from cycloaliphatic or cycloaliphatic-aliphatic carboxylic acids, such as, for example, cyclopropane, cyclobutane, cyclopentane or cyclohexane carboxylic acid, cyclopropyl or cyclobutyl methane carboxylic acid or cyclopentyl or cyclohexyl ether carboxylic acid.
• cycloaliphatic or cycloaliphatic-aliphatic carboxylic acids such as, for example, cyclopropane, cyclobutane, cyclopentane or cyclohexane carboxylic acid, cyclopropyl or cyclobutyl methane carboxylic acid or cyclopentyl or cyclohexyl ether carboxylic acid.
• esterified hydroxy group mentioned is a group derived from one of the longer-chain aliphatic carboxylic acids mentioned below in connection with the group R 2 .
• the free or esterified hydroxyl group can also be present as a substituent in radicals R 1 or R 3 which, as described above, already have ether groups.
• R 1 is the formula has, in which X 4 - X 6 each alkyl or alkenyl having 12-20 C atoms, but X 6 can also be hydrogen, in particular as alkyl or alkenyl. of the groups highlighted above.
• Corresponding compounds with a free hydroxyl group instead of the acyloxy group are also of interest.
• R 2 is a saturated or unsaturated, aliphatic or aliphatic cycloaliphatic hydrocarbon radical with 11-21 C atoms which is optionally also substituted by oxygen functions, ie the acyl radical is derived from saturated or unsaturated, aliphatic, or cyclcaliphatic-aliphatic, optionally oxygenated in the hydrocarbon radical with 12-22, preferably with 14-18 C atoms.
• the saturated or unsaturated fatty acids such as lauric acid, myristic acid, palmitic acid, margarinic acid, stearic acid, arachic acid, oleic acid, elaidic acid, linoleic acid, a- and ⁇ -elaostearic acid, stearolic acid, ⁇ -linolenic acid, and also among the cycloaliphatic-aliphatic, for example, are to be mentioned as such the dihydrosterculic acid, malvalic acid, hydnocarpic acid and chaulmoogras acid.
• Oxygenated acids of this type which are also suitable for the acyl radical, are, for example, those by epoxidation of the resulting olefinic fatty acids and cycloaliphatic-aliphatic acids resulting, for example the , Epoxystearic acid, furthermore derivatives of the abovementioned acids, which have, for example, one or more hydroxyl groups, such as, for example, ricinoleic acid.
• amino acid X or the amino acids of a sequence X according to formula (I) are any D- or L-amino acids in which amino groups and carboxyl groups are bonded to aliphatic C atoms, i.e. one that is not part of an aromatic system.
• amino acids and carboxyl groups are bonded to aliphatic C atoms, i.e. one that is not part of an aromatic system.
• "natural" amino acids i.e. naturally occurring antipodes and analogues.
• the peptide sequence X in the compounds of the formula (I) or in their salts is composed of a maximum of 10 amino acids, preferably at least half carrying a hydrophilic group, such as, in particular, hydroxyl, amino, carboxyl, carbamide, guanidino or Imidazolyl groups.
• ionic amino acids in this category acidic groups, in particular aspartic and glutamic and oxyglutamic acid, should be emphasized, lysine, ornithine, arginine and histidine should be emphasized among basic groups.
• Amino acids with a neutral character are especially the amides, such as asparagine, glutamine and hydroxyl groups, primarily serine and threonine.
• X in formula (I) represents the amino acid mentioned, it is also e.g. bearing one of said hydrophilic groups, e.g. especially serine or threonine.
• amino acids that can go into the above sequence and that do not have hydrophilic groups, especially the unsubstituted ones, such as glycine, alanine, valine, norvaline, leucine, isoleucine, phenylalanine, but also some substituted ones that have a non-hydrophilic character, such as methionine.
• unsubstituted ones such as glycine, alanine, valine, norvaline, leucine, isoleucine, phenylalanine, but also some substituted ones that have a non-hydrophilic character, such as methionine.
• the order of the mentioned amino acids in the peptide chain X may be any, but such Sequen - preferably zen, in which all amino acids are attached with hydrophilic groups directly to one another, and among these, those in which this sequence of hydrophilic amino acids at the carboxyl group of the substituted cysteine or homocysteine part is bound.
• An important group of lipopeptides according to the present invention comprises compounds in which the peptide chain X consists of a maximum of 5 amino acids.
• lipopeptides the following types of lipopeptides should be mentioned in particular: then the corresponding types in which threonine, glutamine or asparagine replace the serine; also the connection types of the type: and the corresponding ones with threonine, glutamine or asparagine as exchange amino acids for serine, further and the amides and carboxylic acid esters with a terminal carbamide or ester group, the compounds in which the acyl radical R 2 -CO-palmitoyl, stearoyl or oleoyl, Z 3 hydrogen and Z 1 and Z 2 alkoxy radicals are to be considered primarily represent, and the same among each other and preferably hexadecyloxy, or octadecyloxy, and those in which Z 1 and Z 2 are different and denote the alkoxy radicals mentioned, and these radicals occur in any combination and / or variation.
• the sequences described can be palmitoyl derivative, furthermore the compounds resulting from the substitution of the serine by threonine, glutamic acid
• the terminal carboxyl group may be in amidated form.
• those which are derived from a primary or secondary amine are also suitable.
• amides of lower aliphatic amines with 1-7 C atoms such as methylamine, ethylamine, propylamine, butylamine, dimethylamine, diethylamine or propyl- and isopropylamine, are also aromatic amines, in particular monocyclic, such as aniline or toluidine, araliphatic, such as Benzylamine or heterocyclic amines, such as the aminopyridines.
• the secondary aliphatic amines can also be ring-closed nitrogen bases, e.g. Pyrrolidine, piperidine or piperazine.
• Specific amides are e.g. the unsubstituted or the methyl, ethyl, dimethyl or diethyl amides of all of the above-mentioned specific lipopeptides according to the present invention or such amides of the compounds described in the illustrative examples.
• the alcohol component is preferably derived from lower aliphatic alcohols with 1-7 C atoms, such as methyl, ethyl, n-propyl, isopropyl or the butyl alcohols.
• the esterifying alcohols can also be polyvalent, such as ethylene glycol or propylene glycol or glycerin.
• araliphatic alcohols especially monocyclic lower aliphatic alcohols with 1-7 C atoms in the aliphatic part, such as benzyl alcohol, or heterocyclic alcohols such as tetrahy drofuranol or tetrahydropyranol can be used for the esterification.
• esters of this type of lipopeptides according to the invention mention may be made, for example, of the methyl, ethyl and ethylene glycol or propylene glycol esters of all of the specific lipopeptides mentioned above or those described in the illustrative examples.
• the present new lipopeptides are, depending on the nature of their substituents, neutral, acidic or basic compounds. If excess acidic groups are present, they form salts with bases such as ammonium salts or salts with alkali or alkaline earth metals, e.g. Sodium, potassium, calcium or magnesium; however, if excess basic groups are present, they form acid addition salts.
• bases such as ammonium salts or salts with alkali or alkaline earth metals, e.g. Sodium, potassium, calcium or magnesium; however, if excess basic groups are present, they form acid addition salts.
• Acid addition salts are particularly pharmaceutically usable, non-toxic acid addition salts, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic, methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenzoic, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or organic sulfonic acids such as methanesulfonic, ethanesulfonic, 2 -Hydroxy-ethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesul
• Complexes are those with metal salts, e.g. compounds formed with heavy metal salts, such as copper, zinc, iron or cobalt salts.
• the phosphates, pyrophosphates and polyphosphates of these metal salts are preferably used to form such complexes, optionally in combination with acidic organic substances, e.g. acidic group-containing polysaccharides, such as carboxymethyl cellulose, tannic acid, polyglutamic acid or partially hydrolyzed gelatin, and also alkali metal polyphosphates such as e.g. "Calgon N", “Calgon 322", “Calgon 188" or "Plyron B 12".
• the compounds of the present invention according to formula (I) above, their salts and complexes and mixtures have valuable pharmacological properties, in particular a pronounced immunopotentiating effect.
• the compounds in the dose range of 0.5-320 ⁇ g / ml stimulate the proliferation of B lymphocytes determined 20 to 50 times in vitro using thymidine incorporation in comparison to non-stimulated control lymphocytes.
• the extent of the stimulation corresponds to that which is achieved with the most effective known B cell mitogens [dextran sulfate, E. coli lipopolysaccharide, PPD (purified protein derivative)], with the new compounds of the present application also high concentrations not being lymphocytotoxic Act.
• the new compounds of the formula (I), their salts and complexes and mixtures are also able to induce the formation of antibody-producing cells in concentrations of 0.3-60 ⁇ g / ml in spleen cell cultures of normal mice (increase in the 19S-plaque-forming Cells a factor of 20 to 50 above the control value (in the absence of the stimulating substances):
• specific antibodies against sheep erythrocytes are formed in the presence of the compounds mentioned, without adding sheep erythrocytes to the cultures for immunization.
• the substances mentioned in the same concentration range can also increase the immunological reactivity of T cell-depleted spleen cell cultures (from congenitally athymic nu / nu mice) compared to a normally thymus-dependent antigen (sheep erythrocytes) (factor 10 to 40 compared to untreated control cultures).
• the compounds mentioned not only directly or indirectly induce proliferation and synthesis performance of B-lymphocytes (ie of potentially antibody-forming cells) in vitro, but also effects on T-lymphocytes (which include regulatory active helper and suppressor cells and cytotoxic effector cells ), conveyed.
• the compounds mentioned in a concentration range of 10-100 ⁇ g / ml can significantly (up to 10 times) potentiate the reactivity of cortisone-resistant thymus cells with allogeneic irradiated stimulator lymphocytes.
• CSA is a biological mediator that is necessary for the differentiation of bone marrow stem cells into macrophages and polymorphonuclear leucocytes.
• the compounds mentioned thus bring about an increased replenishment of cells which are of central importance for the non-specific resistance and for the induction, amplification and expression of specific (lymphocyte-mediated) immune reactions.
• the immunopotentiating effect of the new compounds of the formula (I), their salts or complexes or mixtures can also be demonstrated in vivo: for example, the injection of a lipopeptide according to the invention leads to a high increase in the CSA concentration in the serum within 3-9 hours (up to 120 colonies per 10 5 mouse bone marrow cells after adding chloroform extracted serum [5% final concentration] compared to 0 - 5 colonies in untreated animals). Accordingly, the administration of the same compounds in vivo significantly increases the antibody-producing ability of mice:
• NMRI mice are immunized by intraperitoneal injection of 10 ⁇ g of precipitate-free BSA on day 0. 9.15 and 29 days later, serum samples are taken and their content of anti-BSA antibodies is examined using a passive hemagglutination technique. In the dose used, soluble BSA is subimmunogenic for the recipient animals, ie it is unable to trigger any or only a very slight production of antibodies. Additional treatment of the mice with certain immunopotentiating substances before or after the antigen administration leads to an increase in the antibody titer in the serum. The effect of the treatment is determined by the score achieved, ie expressed by the sum of the log 2 titer differences on the three bleeding days.
• the compounds of the formula (I), their salts or complexes or mixtures are capable of antibody production against five days in a row after intraperitoneal or subcutaneous application of 0.03-3 mg / kg animal before or after immunization with BSA To significantly increase BSA.
• the lipopeptides according to the present invention are also not very toxic: Even 5 intraperitoneal applications in a dose of 10 mg / kg / day on five consecutive days were apparently tolerated without symptoms by mice. Since the doses required for immunostimulation are very small, the therapeutic breadth of the new compound is very large.
• the new lipopeptides according to the present invention can thus significantly increase the cellular and especially the humoral immunity, both in a mixture with the antigen itself (adjuvant effect in the narrower sense) and with a supply that is separate in time and place from the antigen injection (systemic immunopotentiation).
• the new lipopeptides according to the present invention can thus be used as adjuvants in a mixture with vaccines to improve the vaccination success and to improve the protection against infection mediated by humoral antibodies and / or cellular immunity against bacterial, viral or parasitic pathogens.
• the compounds described, in a mixture with various antigens are suitable as adjuvants in the experimental and industrial production of antisera for therapy and diagnosis and in the induction of immunologically activated lymphocyte populations for cell transfer processes.
• the new lipopeptides can be used to promote immune reactions in humans and animals that are already taking place, even without simultaneous antigen supply.
• the compounds are therefore particularly suitable for stimulating the body's defense, for example in the case of chronic and acute infections or in the case of selective (antigen-specific) immunological defects, and also in congenital, but also in acquired general (ie non-antigen-specific) defect states, such as those in old age, in the course of severe primary diseases and especially after therapy with ionizing radiation or with immunosuppressive hormones.
• the substances mentioned can therefore preferably also in combination with Antibiotics, chemotherapy drugs or other healing methods can be administered to counteract immunological damage.
• the substances described are also suitable for the general prophylaxis of infectious diseases in humans and animals.
• the new lipopeptides can be prepared by methods known per se or the new methods described here.
• the protective groups in the process according to variant a) are in particular those known from the synthesis of peptides.
• protective groups for amino groups are acyl or aralkyl groups such as formyl, trifluoroacetyl, Ph t haloyl, benzenesulfonyl, p-toluenesulfonyl, o-nitro - phenylsulfenyl, 2,4-dinitrophenylsulfenyl groups (these sulfenyl groups can also be nucleophilic by the action of Reagents, for example sulfites, thiosulfates, are split off), optionally substituted benzyl or diphenyl or triphenylmethyl groups substituted by lower alkoxy groups, especially o- or p-methoxy groups, or groups derived from carbonic acid, such as in the aromatic rings, eg arylmethyloxycarbonyl groups substituted by halogen atoms such as chlorine or bromine, nitro groups, lower alkyl or lower alkoxy groups or coloring groups, eg
• the amino groups can also be formed by formation of enamines obtained by reacting the amino group with 1,3-diketones, e.g. Benzoylacetone, acetylacetone or dimedone.
• 1,3-diketones e.g. Benzoylacetone, acetylacetone or dimedone.
• Carboxyl groups are protected, for example, by amide or hydrazide formation or by esterification.
• the amide and hydrazide groups can be optionally substituted, the amide group e.g. by the 3,4-dimethoxybenzyl or bis- (p-methoxyphenyl) methyl group, the hydrazide group e.g. by the carbobenzoxy group, the trichloroethyloxycarbonyl group, the trifluoroacetyl group, the trityl group, the tert-butyloxycarbonyl group or the 2- (p-biphenylyl) isopropyloxycarbonyl group.
• Suitable for esterification are e.g.
• lower optionally substituted alkanols such as methanol, ethanol, cyanomethyl alcohol, benzoylmethyl alcohol or in particular tert-butanol, furthermore aralkanols such as aryl lower alkanols, e.g.
• benzyl alcohols or benzhydrols such as benzhydrol, p-nitrobenzyl alcohol, p-methoxybenzyl alcohol, 2,4,6-trimethylbenzyl alcohol optionally substituted by lower alkyl or lower alkoxy groups or halogen atoms, phenols optionally substituted by electron-withdrawing substituents and thiophenols such as thiophenol, thiocresol, p-nitronol 4,5- and 2,4,6-trichlorophenol, pentachlorophenol, p-nitrophenol, 2,4-dinitrophenol, p-cyanophenol or p-methanesulfonylphenol, further, for example N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxypiperidine, 8-hydroxyquinoline.
• the hydroxyl groups of the serine and threonine residues can e.g. be protected by esterification or etherification.
• Suitable acyl radicals in the esterification are, in particular, radicals derived from carbonic acid, such as benzoyloxycarbonyl or ethyloxycarbonyl.
• Groups suitable for etherification are, for example, benzyl, tetrahydropyranyl or tert-butyl radicals.
• Also suitable for protecting the hydroxyl groups are those described in Ber. 100 (1967), 3838-3849 2,2,2-trifluoro-l-tert-butyloxycarbonyl- amino or -1-benzyloxycarbonylaminoethyl groups (Weygand).
• tert-butyl ester group or the benzhydrol group to protect the carboxyl group of the side chains and optionally the terminal carboxyl group
• tert-butyloxycarbonyl group to protect the amino groups of the side chains, for the hydroxyl groups of serine or threonine, the tert. -Butyl ether group and, if desired, the 2,2,2-trifluoro-1-tert-butyloxycarbonylamino-ethyl group to protect the imino group of the histidine.
• the process-related removal of the protective groups with acidic agents under mild conditions is carried out e.g. in a manner known from peptide chemistry, e.g. by treatment with trifluoroacetic acid.
• a special protective group for carboxyl groups which can be split off under neutral conditions, is the group of the general formula described, for example, in German Offenlegungsschrift 27 06 490 wherein R 1 , R 2 and R3 each represent a hydrocarbon radical, where the radicals can also be linked to one another by a simple CC bond, in particular alkyl radicals having 1-5 C atoms.
• Protecting groups of this type are, for example, the 2- (dimethyl-tert-butylsilyl) ethyl, the 2- (dibutyl-niethylsilyl) ethyl and especially the 2- (trimethylsilyl) ethyl group.
• protective groups can also be split off under basic conditions, their cleavage under neutral conditions is particularly, and by the action of a salt of hydrofluoric acid, of interest.
• the protective group is advantageously removed in an aprotic organic solvent; the presence of solvents which are able to solvate the fluoride anion, such as water or lower aliphatic alcohols, is preferably avoided.
• the carboxyl group of the compound (XI) can be converted, for example, into an acid azide, anhydride, imidazolide, isoxazolide or an activated ester, such as cyanomethyl ester, carboxymethyl ester, thiophenyl ester, p-nitrothiophenyl ester, thiocresyl ester, p-methanesulfonylphenyl ester, p-methanesulfonylphenyl ester , 4-dinitrophenyl ester, 2,4,5- or 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 8-hydroxyquinoline ester, 2-hydroxy-1,2-dihydro-1-carbäthoxy- quinoline ester, N-hydroxypiperidine ester or an enol ester obtained with N-ethyl-5-phenyl-isox
• the amino group of the compound ( X II) can be can be activated, for example, by reaction with a phosphite.
• condensations are: the Weygand-WUnsch method (carbodiimide in the presence of N-hydroxysuccinimide), the azide method, the N-carboxyanhydride or N-thiocarboxyanhydride method, the activated ester method and the anhydride method.
• these condensations can be carried out using the Merrifield method.
• free hydroxyl groups in R 1 or the SH group in compounds of the formula XIII are etherified or compounds in compounds of the formula (I) in which, however, no free hydroxyl groups are present in X.
• acylated can be carried out in manner known per se, for example an anhydride or acid halide, preferably ollidin by reaction with a reactive functional derivative of the corresponding carboxylic acid residue to be introduced, such as in the presence of a tertiary base such as pyridine or K. Free amino groups in the part would also be esterified, so that they may have to be protected from the acylation, for example by conversion into a salt, for example into the hydrochloride.
• This process is particularly suitable for the preparation of compounds of the formula (I) in which the acyl groups in the R 1 radical are different from the acyl radical R 2 .
• the etherification of free hydroxyl groups can also be carried out in a manner known per se, for example by treatment with an alkyl or alkenyl halide in the presence of a base, for example silver oxide or, in particular with a diazoalkane, such as a lower aliphatic diazoalkane having 1-3 C atoms, primarily diazomethane, for example in ether solution.
• a base for example silver oxide
• a diazoalkane such as a lower aliphatic diazoalkane having 1-3 C atoms, primarily diazomethane, for example in ether solution.
• This method is particularly suitable for the preparation of compounds having a radical R 1 according to partial formula (VII).
• lipopeptides according to formula I obtained by any of the described process variants, in which a free terminal carboxyl group is present in part X, the same can be used in a manner known per se, e.g. according to one of the methods used in peptide chemistry, into which amide or ester groups are converted.
• lipopeptides according to formula (I) and the subgroups described above those which have the R configuration on the C * atom of the cysteine residue are particularly preferred.
• a compound XI to be used as a starting material, in which W is OH, can be obtained by condensation of the substituted cysteine or homocysteine of the formula wherein R 2 has the same meaning as in formula I, in the presence of a basic agent with a compound of the formula wherein T is a reactive, functionally modified hydroxy group can be obtained.
• the cysteine or homocysteine carboxyl group is temporarily protected by a protective group commonly used in peptide chemistry.
• a reactive, functionally modified hydroxy group T is e.g. an esterified hydroxy group, e.g. one with an aliphatic or aromatic sulfonic acid, e.g. a lower aliphatic sulfonic acid with 1-7 C atoms or a monocyclic aromatic sulfonic acid, such as a benzenesulfonic acid.
• a p-toluenesulfonic acid ester is primarily used as a compound according to formula XV.
• a reactive esterified hydroxy group is also a halogen atom, e.g. Chlorine, bromine or iodine, or in particular an epoxy group.
• a basic medium suitable for carrying out the condensation is a weakly basic or a strongly basic compound, such as, for example, an alkali metal or alkaline earth metal hydride or magnesium hydride, an alkali metal salt of a weak acid, such as sodium or potassium carbonates.
• a weakly basic or a strongly basic compound such as, for example, an alkali metal or alkaline earth metal hydride or magnesium hydride, an alkali metal salt of a weak acid, such as sodium or potassium carbonates.
• silver oxide is a preferred basic medium.
• an alkali metal of a weak acid is also preferably used as the condensing agent, in particular sodium or potassium carbonate.
• the starting material of the formula XVI is treated with an acylating agent which introduces the radical R 2 -CO-, where R has the same meaning as in formula I.
• the conditions for this acylation are the same as for variants d) and e) mentioned above. In particular, care must be taken to ensure that free amino groups in the peptide chain X are converted into salt form, for example into the hydrochloride or into a quaternary ammonium salt.
• amino acids or peptides to be used for the production of the new lipopeptides according to the process are known or can be prepared by methods known per se.
• the not yet mentioned starting compounds for carrying out the above-mentioned processes a) to g) can be prepared in a manner known per se.
• compounds of the formula XVI can be prepared from corresponding compounds in which the amino group is protected, it being possible for the protecting groups to be those which are known from peptide chemistry.
• These compounds can in turn be obtained from the corresponding protected cysteines by reaction with a compound of the formula R1 -T, as described above.
• the lipopeptides obtained can be converted into their salts in a manner known per se, e.g. by reacting acidic compounds obtained with alkali or alkaline earth metal hydroxides or basic compounds obtained with acids.
• the isomer mixtures obtained can be separated in a known manner on the basis of the physico-chemical differences in the constituents, for example by chromatography and / or fractional crystallization. The more effective of the isomers is advantageously isolated.
• the invention also relates to those embodiments of the process in which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or terminates the process at any stage, or forms a starting material under the reaction conditions or in the form of a reactive one Derivative or salt used.
• the starting materials used are preferably those which, according to the process, lead to the compounds described above as being particularly valuable.
• the present invention also relates to pharmaceutical preparations which contain the described new lipopeptides according to the invention, both those corresponding to the formula (I) and those of the formula ( XI ), their mixtures, salts or complexes.
• the pharmaceutical preparations according to the invention are those for enteral, such as oral or rectal, and parenteral administration to warm-blooded animals that contain the pharmacological active ingredient alone or together with a pharmaceutically applicable carrier material.
• the dosage of the active ingredient depends on the warm-blooded species, the age and the individual condition, as well as on the mode of administration.
• the new pharmaceutical preparations contain from about 10% to about 95%, preferably from about 20% to about 90% of the active ingredient.
• Pharmaceutical preparations according to the invention can e.g. in unit dose form, such as coated tablets, tablets, capsules, suppositories or ampoules.
• the pharmaceutical preparations of the present invention are manufactured in a manner known per se, e.g. produced by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
• Suitable carriers are in particular fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and also binders, such as starch paste using, for example, corn, wheat, rice or potato starch, gelatin , Tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and / or, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, auxiliaries are first and foremost Polyethylene glycol.
• fillers such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphate
• Dragee cores are provided with suitable, optionally gastric juice-resistant coatings, including concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings .
• suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate, are used.
• Dyes or pigments can be added to the tablets or dragee coatings, for example for identification or for labeling different doses of active ingredient.
• Example 1 1.25 g of N-palmitoyl-S- [2 (R), 3-dihexadecyloxypropyl] -Cys-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OBu t ) 2 are in 15 ml of 90 percent trifluoroacetic acid were added and the solution was evaporated at 20 ° after 60 minutes. The residue is digested in 5 ml of ethyl acetate and then dried over potassium hydroxide.
• the above starting material is produced as follows: To 1.7 g of N-palmitoyl-S- [2 (R), 3-dihexadecyloxypropyl] - (L) -cysteine and 1.47 g of H-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu- (OBut) 2 in 25 ml of dimethylformamide, 0.475 g of dicyclohexylcarbodiimide and 0.355 g of N-hydroxybenzotriazole are added. After 20 hours at 20 °, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel.
• Chloroform-methanol (99: 1) elutes the pure N-palmitoyl-S42 (R), 3-dihexadecyloxypropyl] -Cys-Ser (Bu t ) -Ser (But) -Phe-Ala-Glu (OBut) 2, whose Rf -Value in the thin layer chromatogram on silica gel is 0.63 (chloroform-methanol 95: 5).
• Example 2 0.95 g of N-palmitoyl-S- [2 (R, S) -hydroxy-octadecyl] -Cys-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OBu t ) 2 are taken up in 10 ml of 90 percent trifluoroacetic acid and the solution is evaporated after 45 minutes at 20 ° under reduced pressure. The residue is digested in water and then dried over potassium hydroxide.
• Example 2 The above starting material is analogous to Example 1 by condensation of N-palmitoyl-S- [2 (R, S) -hydroxy-octadecyl] - (L) -cysteine with H-Ser- (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OBu t ) 2 obtained.
• Example 3 1.1 g of N-palmitoyl-S- [2 (R, S) -palmitoyloxyoctadecyl] -Cys-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OB t ) 2 are taken up in 15 ml of 90 percent trifluoroacetic acid and evaporated after 60 minutes at 20 °. The residue is digested with ethyl acetate and then dried over potassium hydroxide.
• the starting material is produced as follows:
• Chioroform-methanol 98: 2 elute the N-palmitoyl-S- [2 (R, S] -palmitoyloxy-octadecyl] -Cys- Ser- (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OBu t ) 2 with the Rf value 0.48 (chloroform-methanol 95: 5) and 0.74 (157 A) in a thin layer chromatogram on silica gel.
• Example 4 0.98 g of N-palmitoyl-S-netadecyl-Cys-Ser- (Bu t ) -Ser (Bu t ) -Phe-Ala-D-Glu (OBu t ) 2 are dissolved in 10 ml of 90 percent trifluoroacetic acid added. The solution is evaporated after 50 minutes at 20 ° under reduced pressure and the residue is dried over potassium hydroxide. The N-palmitoyl-S-octadecyl-Cys-Ser-Ser-Phe-Ala-D -Glu-OH with the Rf value 0.43 (157 c) is obtained in a thin layer chromatogram on silica gel.
• H-Ser- (Bu t ) -Ser (Bu t ) -Asn-Ala-D-Glu (OBu t ) 2 is prepared in an analogous manner.
• Example 5 1.4 g of N-palmitoyl-S- [2 (R, S), 3-dihexadecyloxypropyl] - (D, L) homocysteinyl-Ser (Bu t ) -Ser (Bu t ) -Asn-Ala-Glu (OBu t ) 2 are taken up in 15 ml of 90 percent trifluoroacetic acid and evaporated after 50 minutes at 20 °. The residue is dried over potassium hydroxide.
• N-Plamitoyl-S- [2 (R, S), 3-dihexadecyloxypropyl] - (D, L) homocysteinyl-Ser-Asn-Ala-Glu-OH is obtained as a wax product.
• the starting material can be prepared from N-palmitoyl-S- [2 (R, S), 3-dihexadecyloxypropyl] - (D, L) homocysteine and H-Ser (Bu t ) -Ser- according to the methodology described in Examples 1 to 4.
• (Bu t ) -Asn-Ala-Glu (OBu t ) 2 can be obtained.
• Example 6 1.2 g N, S-dipalmitoyl (L) -Cys-Ser (Bu t) -Ser (Bu t) -Phe-Ala-GLW (OBu t) 2 in 15 ml 90 percent trifluoroacetic acetic acid deblocked for 45 minutes. Evaporation of the trifluoroacetic acid gives N, S-dipalmitoyl-Cys-Ser-Ser-Phen-Ala-Glu-OH.
• the starting material is obtained as in Examples 1 to 4 from N, S-dipalmitoyl- (L) -cysteine and H-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OBu t ) 2 .
• Example 7 If one starts from N-palitoyl-S- [2 (R), 3-dihexadecyloxypropyl] - (L) -cysteine, N-palmitoyl-S- [2 (R, S) -hydroxy-octa-ecyl] - (L) -cysteine, N-palmitoyl-S- [2 (R, S) -palmitoyloxy-octadecyl] - (L) -cysteine, N-palmitoyl-S-octadecyl- (L) -cysteine, N-palmitoyl-S - [2 (R, S), 3-dihexadepyloxypropyl] - (D, L) -homocysteinef N, S-dipalmitoyl-L - cysteine, N-palmitoyl-S- [2 (R, S) -pal
• Example 8 The substituted cysteines used as starting materials in the preceding or following examples can e.g. are obtained as follows:
• N-palmitoyl (L) -cysteine is added to 41.5 mg of N atriumhy- hydride dispersion in about 5 ml of absolute dioxane, and can react to completion at 0 ° under nitrogen until evolution of hydrogen finished.
• 330 mg of 1-tosyl-2 (R), 3-dihexadecylglycerol in 2 ml of dioxane are added and the mixture is heated at 90 ° for 15 hours. The mixture is then evaporated, acidified to pH approx. 3 with 1N HCl and distributed between chloroform and water. The chloroform phase is dried and evaporated and the residue is purified on 9 g silica gel Merck in chloroform / acetone 8: 2.
• N-palmitoyl-S- [2 (R, S) -palmitoyloxyoctadecyl] - ( L ) -cysteine-benzhydryl ester is dissolved at room temperature in a mixture of 0.4 ml of trifluoroacetic acid and 1.6 ml of methylene chloride and 2 Hours react. It is evaporated to the dry state in a vacuum, the residue is dissolved in chloroform and the chloroform phase is shaken out several times with water.
• the starting material is obtained as follows: 0.8 g of N-palmitoyl-S- [2 (R, S) -hydroxy-octadecyl] - (L) -cysteine-benzhydryl ester in 5 ml of pyridine is mixed with 0.56 ml of palmitic acid chloride 5 ml methylene chloride. After 24 hours at room temperature, the acylation according to the thin layer chromatogram (silica gel Merck, chloroform) has ended. 2 ml of methanol are added to the reaction solution and the mixture is evaporated in vacuo after 20 minutes.
• N-palmitoyl-S-dodecyl- (L) -cysteine is obtained in the same way.
• N-palmitoyl-S- [cholesteryl- (3)] - (L) -cysteine is obtained analogously from N-palmitoyl- (L) -cysteine and cholesteryl-p-toluenesulfonate.
• N-palmitoyl-S- (3,6-dioxa-docosanyl) - (L) -cysteine give the N-palmitoyl-S- (3,6-dioxa-docosanyl) - (L) -cysteine .
• the p-toluenesulfonate of retinol gives analogously N-palmitoyl-S-retinyl- (L) -cysteine
• the p-toluenesulfonate of phytol gives analogously N-palmitoyl-S-phytyl- (L) -cysteine.
• Example 10 N-Palmitoyl-S- [2 (R, S), 3-dihexadecyloxypropyl] - (L, D) -homo-cysteine.
• Example 11 1.5 g of N, S-dipalmitoyl-Cys-Ser (Bu t ) -Ser (Bu t ) -Asn-Ala-Pro-NH 2 are dissolved in 15 ml of 90% trifluoroacetic acid and the solution after 45 minutes evaporated at room temperature. The residue is dried over potassium hydroxide.
• the N, S-dipalmitoyl-Cys-Ser-Ser-Asn-Ala-Pro-NH 2 thus obtained is a white powder and has a Rf value of 0.50 (157 c) in a thin layer chromatogram on silica gel.
• the starting material can be obtained from N, S-dipalmitoyl- (L) -cysteine and H-Ser (Bu t ) -Ser (Bu t ) -Asn-Ala-Pro-NH 2 using the methodology described in Examples 1 to 4 .
• the Rf value in the thin layer chromatogram (chloroform-methanol 9: 1) is 0.20.
• H-Ser (Bu t ) -Ser (Bu t ) -Asn-Ala-Val-OCH 3 can be prepared analogously to the production of H-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-D-Glu (OBu t ) 2 can be obtained in Example 4.
• [Rf value in the thin layer chromatogram on silica gel 0.43 (157 c)].
• Example 13 1.2 g of N-palmitoyl-S-octadecyl-D-Cys-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OBu t ) 2 are dissolved in 12 ml of 90% trifluoroacetic acid and the Solution evaporated after standing for 45 minutes at room temperature. The residue is digested with petroleum ether and dried over potassium hydroxide. N-Palmitoyl-S-octadecyl-D-Cys-Ser-Ser-Phe-Ala-Glu-OH is obtained as a white powder. Rf value in a thin layer chromatogram on silica gel 0.38 (157 c).
• the starting material can be prepared from N-palmitoyl-S-octadecyl- by the method described in Examples 1 to 4. cysteine and H-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OBu t ) 2 . Rf value in the thin layer chromatogram 0.70 (157 a).
• the starting compound can be prepared from N-palmitoyl-S-octadecyl- (L, D) -homocysteine and H-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (according to the methodology described in Examples 1 to 4 OBu t ) 2 can be obtained.
• Rf value in a thin layer chromatogram on silica gel 0.75 (157 a).
• Example 15 1.1 g of N-palmitoyl-S-farnesyl-Cys-Ser (Bu t) - S he (Bu t) -Phe-Ala-Glu (OBu t) 2 are dissolved in 10 ml 90 percent trifluoroacetic acid and the solution was evaporated to dryness after 40 minutes. The residue is digested in ethyl acetate and dried over potassium hydroxide. N-Palmitoyl-S-farnesyl-Cys-Ser-Ser-Phe-Ala-Glu-OH is obtained as a white powder. Rf value in a thin layer chromatogram on silica gel 0.35 (157 c).
• the starting compound can be prepared according to the methodology described in Examples 1 to 4 from N-palmitoyl-S-farnesyl- (L) -cysteine and H-Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OBu t ) 2 can be won.
• Example 16 Starting from the N-palmitoyl-S-octadecyl- (D) -cysteine, N-palmitoyl-S-octadecyl- (L, D) -homocysteine and N-palmitoyl-S- farnesyl- (L) -cysteine, which are hereinafter referred to in this order as the compounds C S OH, C 9 OH and C 10 OH, where OH is the hydroxyl group of the free carboxyl function, and condenses each of these compounds with the the following peptides using the same protective groups as in Examples 1 to 4 and using the same method, the following lipopeptides are obtained:
• Example 17 5 g (13.9 mmol) of N-palmitoyl- (L) -cysteine and 4.76 g (16.7 mmol - 1.2 equivalents) of farnesyl bromide are dissolved in 50 ml of ethanol and, after cooling to 25 °, are added Add 4.8 g of potash and heat at about 60 ° for 9 hours under nitrogen; then 5 ml of ethanol are added and the mixture is heated at 70 ° for a further 6 hours. It is then evaporated to the dry state in a vacuum, acidified with 2N hydrochloric acid and mixed with ethyl acetate and water. To remove the mineral acid, the ethyl acetate phase is shaken out several times with water.
• N-palmitoyl-S-octadecyl- (D) -cysteine can be produced as follows:
• N-Palmitoyl-S-octadecyl- (L, D) -homocysteine can be obtained in the following way:
• Example 18 An advantageously applicable form for parenteral, preferably subcutaneous administration of the lipopeptides is obtained in the following way:
• the bromide of the non-ethylene glycol monomethyl ether is obtained from 10 g non-ethylene glycol monomethyl ether with 0.87 ml PBr 3 and 0.44 ml pyridine abs. in 6 ml ether abs.
• the components are mixed at -10 ° to -5 ° and then stirred for 16 hours at room temperature.
• 30 ml of a mixture of chloroform and ether (1: 1) are then added, the undissolved material is filtered off with suction and the filtrate is concentrated in vacuo to an oil. The connection is used raw in the next stage.
• N-Palmitoyl-S - [(3,6,9,12,15,18,21,24,27-nona-oxa) -octacosanyl] -Cys-Ser-Ser-Phe-Ala-Glu-OH is obtained as White dust.
• the starting material can be prepared according to the methodology described in Examples 1 to 4 from N-palmitoyl-S - [(3,6,9,12,15,18,21, 24,27-nonaoxa) -octacosanyl] -cysteine and H- Ser (Bu t ) -Ser (Bu t ) -Phe-Ala-Glu (OBu t ) 2 can be obtained.

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